Identifying genes that predispose to type 2 diabetes (T2D) continues to shed light on the mechanism of the origins of the disease and its complications and point to unexpected routes to prevention and improved management. Asian Indians, 25% of the global population, comprise the highest numbers of diabetics in the world. But, the high frequency of diabetes and cardiovascular disease in Asian Indians is difficult to explain, since they lack the traditional risk factors established in Caucasians (smoking and high cholesterol, high meat diet, and high body mass index). Family and migrant studies of Indians point to important genetic components. Some recently identified loci by performing a genome-wide association scan (GWAS) in Euro-Caucasians have not been replicated in non-Caucasians, suggesting that genetic variation in some loci could be restricted to a particular genetic background and environment. The objective of this project is to identify additional susceptibility genes for T2D by performing GWAS in a unique population of Indian Asian Khatri Sikhs, and replicating findings in a large cohort of Asian Sikhs from UK. As compared to the US populations, where population heterogeneity may obscure true association signals and give spurious results, our study has a unique advantage since it is drawn from an endogamous caste group enriched with disease. We hypothesize that there are population-specific functional gene variants that predispose Indian Sikhs to T2D. We propose two specific aims: 1) (a) To conduct a GWAS using a Human610-Quad BeadChip panel on 1,000 T2D cases and 1,030 controls, and (b) to carry out association analyses to map the locations of T2D susceptibility loci. 2) (a) To perform genotyping of the most promising loci identified by GWAS using Illumina's iSelect Infinium Custom Genotyping BeadChip in a large independently collected replication cohort of 7,000 Sikhs from UK, and (b) to perform association analysis to confirm the significant association in the replication cohort. We believe that our study is unique and novel, and promises to yield new information on genetics of diabetes that may be important beyond Indians. PUBLIC HEALTH RELEVANCE: This study is aimed to investigate the underlying causes of genetic predisposition to type 2 diabetes (T2D) in Asian Indians. The proposed study has strong public health relevance as it is focused on a population where T2D has reached to epidemic scale and information on genetic epidemiological aspects hardly exists. Searching genes that predispose to T2D continues to shed light on the mechanism of the origins of the disease and its complications and point to unexpected routes to prevention and improved management. Identifying the susceptibility loci in a population with high diabetic/cardiovascular risk may be important beyond Indians and will increase our understanding of the disease in other groups.